Hypercholesteremia, high blood pressure and smoking are known as three major, dangerous factors causing ischemic diseases. Adequate control of cholesterol concentration in blood is remarkably important for the prophylaxis or therapy of, not only ischemic diseases, but also coronary sclerosis.
Abnormal elevations of lipid levels in the serum or the plasma are called hyperlipidemia or hyperlipemia. There are various lipids, such as cholesterol (cholesteryl ester and free cholesterol), phospholipids (lecithin, sphingomyelin and so on), triglyceride, free fatty acids and other sterols in the serum or the plasma. Especially cholesterol and triglyceride are clinically important among them.
Therefore, it is important to control blood lipid levels within normal range for the treatment and the prevention of various diseases related to atherosclerosis, such as coronary heart disease and cerebral infarction. Hypertriglyceridemia is also related to the development of pancreatitis.
As pharmaceutical compositions for lowering cholesterol in blood, attention has been drawn to those for controlling the biosynthesis of cholesterol, besides those of inhibiting its absorption by binding bile acid including, among others, cholestyramine, colestipol (disclosed in, for example, U.S. Pat. No. 4,027,009), and those of suppressing the intestinal absorption of cholesterol by inhibiting acyl coenzyme A cholesterol acyl transferase (ACAT) including melinamide (disclosed in French Patent No.1476569). As pharmaceutical preparations for controlling the biosynthesis of cholesterol, lovastatin (disclosed in U.S. Pat. No. 4,231,938), simvastatin (disclosed in U.S. Pat. No. 4,444,784), pravastatin (U.S. Pat. No. 4,346,227), etc., which are capable of inhibiting especially 3-hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase, are provided for medicinal use. However, when HMG-COA reductase is inhibited, not only the biosynthesis of cholesterol but the biosynthesis of some other components such ubiquinone, dolichol and heme A, which are necessary for the living body, is also inhibited, so that occurrences of undesirable side effects to be caused thereby are feared.
Squalene synthetase is the enzyme involved in the committed step of the de novo cholesterol biosynthetic pathway. This enzyme catalyzes the reductive dimerization of two molecules of farnesyl pyrophosphate to form squalene.
On the other hand, the compounds expected as inhibitors of cholesterol biosynthesis by inhibiting squalene synthetase are disclosed in JPA H1(1989)-213288, JPA H2(1990)-101088, JPA H2(1990)-235820, JPA H2(1990)-235821, JPA H3(1991)-20226, JPA H3(1991)68591, JPA H3(1991)-48288, U.S. Pat. No. 5,019,390, Journal of Medicinal Chemistry, 51 (10), p.1869-1871 (1988), U.S. Pat. No. 5,135,935 and WO 9215579.
Also, the compounds expected as inhibitors of fungal growth by inhibiting squalene synthetase are disclosed in JPA H4 (1992)-279589, EP 475706-A, EP 494622-A and EP 503520-A.
Among 4,1-benzoxazepine derivatives, in 4,1-benzoxazepin-2-one derivatives in which 2-position is substituted with a ketone group, those in which one of the hydrogen atoms at 3-position is replaced with a different substituent, are disclosed in JPA S57(1982)345765 and Chem. Pharm. Bull., 34, 140 (1986).
Ubiquinone, dolichol and heme A have been known as being synthesized from farnesyl pyrophosphate along the cholesterol biosynthesis pathway. Therefore, for avoiding occurrence of side effects due to loss of these substances, it is desirable to inhibit enzymes subsequent to farnesyl pyrophosphate, especially squalene synthetase, in the cholesterol biosynthetic pathway.
In addition, fabric acid derivatives, such as clofibrate (British patent No. 860303) and phenofibrate (Germany patent No. 2250327), are on the market as hypotriglyceridemic agents. But, caution is claimed against the combination therapy of fibrates with statins because of the heightened risk of myopathy and rhabdomyolysis.
Hyperlipidemia or hyperlipoproteinemia is classified by WHO as follows:
Type I: Hyperchyromicronemia PA1 Type IIa: Hyper low density lipoproteinemia (Hypercholesterolemia) PA1 Type IIb: Mixed-type hyperlipidemia which shows increases in low density lipoprotein and very low density lipoprotein PA1 Type III: Abnormal .beta.-lipoproteinemia which shows the presence of .beta.-very low density lipoprotein PA1 Type IV: Hyper very low density lipoproteinemia (Hypertriglyceridemia) PA1 Type V: Mixed-type hyperlipemia which shows increases in very low density lipoprotein and chyromicron PA1 (1) 4,1-Benzoxazepin-2-one derivatives represented by the formula (I): ##STR3## wherein R.sub.1 stands for hydrogen atom or an optionally substituted hydrocarbon group; R.sub.2 and R.sub.3 independently stand for hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group; X stands for a bond or a spacer having the chain length of 1 to 7 atoms; Y stands for an optionally esterified or thioesterified carboxyl group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted carbamoyl group or a N-containing heterocyclic residue having hydrogen atom capable of being deprotonated; provided that, when X is methylene and R.sub.1 is not an alkyl group having carbon atoms of more than 4, Y is neither carboxyl group nor alkoxycarbonyl group; and the ring A may optionally be substituted, or salts thereof, PA1 (2) 4,1-Benzoxazepin-2-one derivatives represented by the formula (I'): ##STR4## wherein R.sup.1 stands for hydrogen atom or an optionally substituted hydrocarbon group; R.sub.2 and R.sub.3 independently stand for hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group; X stands for a bond or a spacer having the chain length of 1 to 7 atoms; Y stands for an optionally esterified or thioesterified carboxyl group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted carbamoyl group or a N-containing heterocyclic residue having hydrogen atom capable of being deprotonated; provided that, when X is methylene, Y is neither carboxyl group nor alkoxycarbonyl group; and the ring A may optionally be substituted, or salts thereof, PA1 (3) a squalene synthetase inhibitor comprising as an active ingredient a 4,1-Benzoxazepin-2-one derivative represented by the formula (I"): ##STR5## wherein R.sup.1 stands for hydrogen atom or an optionally substituted hydrocarbon group; R.sub.2 and R.sub.3 independently stand for hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group; X stands for a bond or a spacer having the chain length of 1 to 7 atoms; Y stands for an optionally esterified or thioesterified carboxyl group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted carbamoyl group or a N-containing heterocyclic residue having hydrogen atom capable of being deprotonated; and the ring A may optionally be substituted, or a salt thereof, and PA1 (4) a fungal growth inhibitor comprising as an active ingredient a 4,1-Benzoxazepin-2-one derivative represented by the formula (I"): ##STR6## wherein R.sup.1 stands for hydrogen atom or an optionally substituted hydrocarbon group; R.sub.2 and R.sub.3 independently stand for hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted phenyl group or an optionally substituted aromatic heterocyclic group; X stands for a bond or a spacer having the chain length of 1 to 7 atoms; Y stands for an optionally esterified or thioesterified carboxyl group, an optionally substituted hydroxyl group, an optionally substituted amino group, an optionally substituted phenyl group, an optionally substituted carbamoyl group or a N-containing heterocyclic residue having hydrogen atom capable of being deprotonated; and the ring A may optionally be substituted, or a salt thereof.